Ureylene naphthalene sulfonic acids

ABSTRACT

Ureylenebis substituted phenylenecarbonylimino symmetrical phenenylbiscarbonylimino dinaphthalenepoly-sulfonic acid salts, and nitro and amino substituted benzamido phenylenedicarbonyl dinaphthalenepoly-sulfonic acid salts that are new intermediates for the preparation of the active ureides, which have complement inhibiting activity.

DESCRIPTION OF THE INVENTION

This invention is concerned with dinaphthalene sulfonic acid urylenesalts, having complement inhibiting activity, of general formula I:##STR1## wherein A is a pharmaceutically acceptable salt cation.

This invention is also concerned with compounds of the formula II:##STR2## wherein R is selected from the group consisting of nitro andamino; and A is selected from the group consisting of alkali metal.These compounds are useful as intermediates for the preparation of thecomplement inhibiting compounds described hereinabove. The intermediatecompounds also possess complement inhibiting activity. The compounds ofthe present invention may be prepared by the following method outlinedin Flow Chart A. ##STR3##

The novel intermediate nitro (I) and amine (II) compounds of theinvention are prepared by reacting 8-amino-1,3,-6-naphthalenetrisulfonicacid trialkali metal salt with 5-nitroisophthaloyl chloride in basicaqueous medium for one hour. After acidification with hydrochloric acid,the solution is diluted with ethanol to provide the8,8'-[(5-nitro-1,3-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonicacid hexa alkali metal salt. Hydrogenation of the nitro-hexa alkalimetal salt using 10% palladium-carbon catalyst, filtration,concentration and treatment with absolute ethanol provides the8,8'-[(5-amino-m-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonicacid hexa alkali metal salt. The amino hexa alkali metal salt is reactedwith a 20% excess of 4-nitro-2-sulfobenzoic acid anhydride in aqueousmedium with alkali metal acetate as a buffer at 0°-5° C. for 15-30minutes. Filtration and acidification of the filtrate with hydrochloricacid followed by warming and dilution with ethanol provides8,8'-[5-(4-nitro-2-sulfobenzamido)-1,3-phenylenedicarbonyl]di-1,3,6-naphthalenetrisulfonicacid hepta alkali metal salt (I). Hydrogenation of (I) using 10%palladium-carbon catalyst in water, filtration and concentration of thefiltrate followed by dilution with ethanol and cooling yields the8,8'-[5-(4-amino-2-sulfobenzamido)-1,3-phenylenedicarbonyl]di-1,3,6-naphthalenetrisulfonic acid heptaalkali metal salt (II). Phosgenation of (II) in aqueous medium withalkali metal carbonate until the solution is weakly basic followed bydilution with ethanol yields8,8',8",8'"-{ureylenebis[(2-sulfo-4,1-phenylene)carbonylimino-s-phenenylbis(carbonylimino)]}tetra-1,3,6-naphthalenetrisulfonicacid tetradecyl alkali metal salt (III).

The term "complement" refers to a complex group of proteins in bodyfluids that, working together with antibodies or other factors, play animportant role as mediators of immune, allergic, immunochemical and/orimmunopathological reactions. The reactions in which complementparticipates take place in blood serum or in other body fluids, andhence are considered to be humoral reactions.

With regard to human blood, there are at present more than 11 proteinsin the complement system. These complement proteins are designated bythe letter C and by number: C1, C2, C3 and so on up to C9. Thecomplement protein C1 is actually an assembly of subunits designatedC1q, C1r and C1s. The numbers assigned to the complement proteinsreflect the sequence in which they become active, with the exception ofcomplement protein C4, which reacts after C1 and before C2. Thenumerical assignments for the proteins in the complement system weremade before the reaction sequence was fully understood. A more detaileddiscussion of the complement system and its role in body processes canbe found in, for example, Bull. World Health Org., 39, 935-938 (1968);Ann. Rev. Medicine, 19, 1-24 (1968); The John Hopkins Med. J., 128,57-74 (1971); Harvey Lectures, 66, 75-104 (1972); The New EnglandJournal of Medicine, 287, 452-454; 489-495; 545-549; 592-596; 642-646(1972); Scientific American, 229, (No. 5 ), 54-66 (1973); FederationProceedings, 32, 134-137 (1973); Medical World News, October 11, 1974,pp. 53-58; 64-66; J. Allergy Clin. Immunol., 53, 298-302 (1974); ColdSpring Harbor Conf. Cell Proliferation 2/Proteases Biol. Control/229-241(1975); Annals of Internal Medicine, 84, 580-593 (1976); "Complement:Mechanisms and Functions", Prentice-Hall, Englewood Cliffs, N. J.(1976).

The complement system can be considered to consist of three sub-systems:(1) a recognition unit (C1q) which enables it to combine with antibodymolecules that have detected a foreign invader; (2) an activation unit(C1r, C1s, C2, C4, C3) which prepares a site on the neighboringmembrane; and (3) and attack unit (C5, C6, C7, C8 and C9) which createsa "hole" in the membrane. The membrane attack unit is non-specific; itdestroys invaders only because it is generated in their neighborhood. Inorder to minimize damage to the host's own cells, its activity must belimited in time. This limitation is accomplished partly by thespontaneous decay of activated complement and partly by interference byinhibitors and destructive enzymes. The control of complement, however,is not perfect, and there are times when damage is done to the host'scells. Immunity is therefore a double-edged sword.

Activation of the complement system also accelerates blood clotting.This action comes about by way of the complement-mediated release of aclotting factor from platelets. The biologically active complementfragments and complexes can become involved in reactions that damage thehost's cells, and these pathogenic reactions can result in thedevelopment of immune-complex diseases. For example, in some forms ofnephritis, complement damages the basal membrane of the kidney,resulting in the escape of protein from the blood into the urine. Thedisease disseminated lupus erythematosus belongs in this category; itssymptoms include nephritis, visceral lesions and skin eruptions. Thetreatment of diphtheria or tetanus with the injection of large amountsof antitoxin sometimes results in serum sickness, an immune-complexdisease. Rheumatoid arthritis also involves immune complexes. Likedisseminated lupus erythematosus, it is an autoimmune disease in whichthe disease symptoms are caused by pathological effects of the immunesystem in the host's tissues. In summary, the complement system has beenshown to be involved with inflammation, coagulation, fibrinolysis,antibody-antigen reactions and other metabolic processes.

In the presence of antibody-antigen complexes the complement proteinsare involved in a series of reactions which may lead to irreversiblemembrane damage if they occur in the vicinity of biological membranes.Thus, while complement constitutes a part of the body's defensemechanism against infection it also results in inflammation and tissuedamage in the immunopathological process. The nature of certain of thecomplement proteins, suggestions regarding the mode of complementbinding to biological membranes and the manner in which complementeffects membrane damage are discussed in Annual Review in Biochemistry,38, 389 (1969).

A variety of substances have been disclosed as inhibiting the complementsystem, i.e., as complement inhibitors. For example, the compounds3,3'-ureylenebis-[6-(2-amino-8-hydroxy-6-sulfo-1-naphthylazo)]benzenesulfonicacid, tetrasodium salt (chlorazol fast pink), heparin and a sulphateddextran have been reported to have an anticomplementary effect, BritishJournal of Experimental Pathology, 33, 327-339 (1952). The compound8-(3-benzamido-4-methylbenzamido)naphthalene-1,3,5-trisulfonic acid(Suramin) is described as a competitive inhibitor of the complementsystem, Clin. Exp. Immunol., 10, 127-138 (1972). German Pat. No.2,254,893 or South African Pat. No. 727,923 discloses certain1-(diphenylmethyl)-4-(3-phenylallyl)piperazines useful as complementinhibitors. Other chemical compounds having complement inhibitingactivity are disclosed in, for example, Journal of Medicinal Chemistry,12, 415-419; 902-905; 1049-1052; 1053-1056 (1969); Canadian Journal ofBiochemistry, 47, 547-552 (1969); The Journal of Immunology, 93, 629-640(1964); The Journal of Immunology, 104, 279-288 (1970); The Journal ofImmunology, 106, 241-245 (1971); and The Journal of Immunology, 111,1061-1066 (1973).

It has been reported that the known complement inhibitorsepsilon-aminocaproic acid, Suramin and tranexamic acid all have beenused with success in the treatment of hereditary angioneurotic edema, adisease state resulting from an inherited deficiency or lack of functionof the serum inhibitor of the activated first component of complement(C1 inhibitor), The New England Journal of Medicine, 286, 808-812(1972). It has also been reported that the drug,pentosan-poly-sulfoester, has an anticomplementary activity on humanserum both in vitro and in vivo, as judged by the reduction in totalhemolytic complement activity; Pathologie Biologie, 25, 33-36 (1977).

The compounds of the present invention may be administered internally,e.g., orally, intra-articularly or parenterally, e.g., intra-articular,to a warm-blooded animal to inhibit complement in the body fluid of theanimal, such inhibition being useful in the amelioration or preventionof those reactions dependent upon the function of complement, such asinflammatory process and cell membrane damage induced byantigen-antibody complexes. A range of doses may be employed dependingon the mode of administration, the condition being treated and theparticular compound being used. For example, for intravenous orsubcutaneous use from about 5 to about 50 mg/kg/day, or every six hoursfor more rapidly excreted salts, may be used. For intra-articular usefor large joints such as the knee, from about 2 to about 20 mg/joint perweek may be used, with proportionally smaller doses for smaller joints.The dosage range is to be adjusted to provide optimum therapeuticresponse in the warm-blooded animal being treated. In general, theamount of compound administered can vary over a wide range to providefrom about 5 mg/kg to about 100 mg/kg of body weight of animal per day.The usual daily dosage for a 70 kg subject may vary from about 350 mg toabout 3.5 g. Unit doses of the acid or salt can contain from about 0.5mg to about 500 mg.

While in general the sodium salts of the acids of the invention aresuitable for parenteral use, other salts may also be prepared, such asthose of primary amines, e.g., ethylamine; secondary amines, e.g.,diethylamine or diethanol amine; tertiary amines, e.g., pyridine ortriethylamine or 2-dimethylaminomethyl-dibenzofuran; aliphatic diamines,e.g., decamethylenediamine; and aromatic diamines, can be prepared. Someof these are soluble in water, others are soluble in saline solution,and still others are insoluble and can be used for purposes of preparingsuspensions for injection. Furthermore as well as the sodium salt, thoseof the alkali metals, such as potassium and lithium; of ammonia; and ofthe alkaline earth metals, such as calcium or magnesium, may beemployed. It will be apparent, therefore, that these salts embrace, ingeneral derivatives of salt-forming cations.

In therapeutic use, the compounds of this invention may be administeredin the form of conventional pharmaceutical compositions. Suchcompositions may be formulated so as to be suitable for oral orparenteral administration. The active ingredient may be combined inadmixture with a pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, i.e., oral or parenteral. The compounds canbe used in compositions such as tablets. Here, the principal activeingredient is mixed with conventional tabletting ingredients such ascorn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesiumstearate, dicalcium phosphate, gums, or similar materials as non-toxicpharmaceutically acceptable diluents or carriers. The tablets or pillsof the novel compositions can be laminated or otherwise compounded toprovide a dosage form affording the advantage of prolonged or delayedaction or predetermined successive action of the enclosed medication.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids ormixtures of polymeric acids with such materials as shellac, shellac andcetyl alcohol, cellulose acetate and the like. A particularlyadvantageous enteric coating comprises a styrene maleic acid copolymertogether with known materials contributing to the enteric properties ofthe coating. The tablet or pill may be colored through the use of anappropriate non-toxic dye, so as to provide a pleasing appearance.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration include suitableflavored emulsions with edible oils, such as, cottonseed oil, sesameoil, coconut oil, peanut oil, and the like, as well as elixirs andsimilar pharmaceutical vehicles. Sterile suspensions or solutions can beprepared for parenteral use. Isotonic preparations containing suitablepreservations are also desirable for injection use.

The term dosage form, as described herein, refers to physically discreteunits suitable as unitary dosage for warm-blooded animal subjects, eachunit containing a predetermined quantity of active component calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical diluent, carrier or vehicle. The specificationfor the novel dosage forms of this invention are indicated bycharacteristics of the active component and the particular therapeuticeffect to be achieved or the limitations inherent in the art ofcompounding such an active component for therapeutic use in warm-bloodedanimals as disclosed in this specification. Examples of suitable oraldosage forms in accord with this invention are tablets, capsules, pills,powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls,ampules, vials, segregated multiples of any of the foregoing and otherforms as herein described.

The complement inhibiting activity of the compounds of this inventionhas been demonstrated by one or more of the following identified tests:(i) Test, Code 026 (C1 inhibitor) - This test measures the ability ofactivated human C1 to destroy fluid phase human C2 in the presence of C4and appropriate dilutions of the test compound. An active inhibitorprotects C2 from C1 and C4; (ii) Test, Code 035 (C3-C9 inhibitor) - Thistest determines the ability of the late components of human complement(C3-C9) to lyse EAC 142 in the presence of appropriate dilutions of thetest compound. An active inhibitor protects EAC 142 from lysis by humanC3-C9; (iii) Test, Code 036 (C-Shunt inhibitor) - In this test humanerythrocytes rendered fragile are lysed in autologous serum via theshunt pathway activated by cobra venom factor in the presence ofappropriate dilutions of the test compound. Inhibition of the shuntpathway results in failure of lysis; (iv) Forssman Vasculitis Test -Here, the well known complement dependent lesion, Forssman vasculitis,is produced in guinea pigs by intradermal injection of rabbitanti-Forssman antiserum. The lesion is measured in terms of diameter,edema and hemorrhage and the extent to which a combined index of theseis inhibited by prior intraperitoneal injection of the test compound at200 mg/kg is then reported, unless otherwise stated; (v) Forssman ShockTest - Lethal shock is produced in guinea pigs by an i.v. injection ofanti-Forssman antiserum and the harmonic mean death time of treatedguinea pigs is compared with that of simultaneous controls; (vi)Complement Level Reduction Test - In this test, the above dosed guineapigs, or others, are bled for serum and the complement level isdetermined in undiluted serum by the capillary tube method of U.S. Pat.No. 3,876,376 and compared to undosed control guinea pigs; and (vii) Cap50 Test -- Here, appropriate amounts of the test compound are added to apool of guinea pig serum in vitro, after which the undiluted serumcapillary tube assay referred to above is run. The concentration ofcompound inhibiting 50% is reported.

With reference to Table I, guinea pigs weighing about 300 g were dosedintravenously (i.v.) or intraperitoneally (i.p.) with 200 mg/kg of thetest compound dissolved in saline and adjusted to pH 7-8. One hour afterdosing, the guinea pigs were decapitated, blood was collected and theserum separated. The serum was tested for whole complement using thecapillary tube assay. Percent inhibition was calculated by comparisonwith simultaneous controls. The results appear in Table I together withresults of tests, code 026, 035, 036, Cap 50, % inhibition and Forssmanshock. Table I shows that the compounds of the invention possess highlysignificant in vitro and in vivo, complement inhibiting activity inwarm-blooded animals.

Table II shows the complement inhibiting activity of the intermediatecompounds of the invention.

                                      TABLE I                                     __________________________________________________________________________    Biological Activities                                                                                                In Vivo Activity                                                              (Guinea Pig)                                                                  % Inhibition                                               Cl  C-Late                                                                            Shunt Inhi-                                                                              Intravenous                                                026*                                                                              035*                                                                              bition 036*                                                                              Time(minutes)                          Compound            Wells                                                                             Wells                                                                             Wells Cap 50*                                                                            2  30 20                               __________________________________________________________________________    8,8',8",8'"-{Ureylenebis[(2-sulfo-4,1-                                        phenylene)carbonylimino-s-phenylbis-                                                              +8  +5  +5    87   -97                                                                              -96                                                                              -95                              (carbonylimino)]}tetra-1,3,6-naphthalene-                                     trisulfonic acid tetradecyl sodium salt                                       __________________________________________________________________________     *Code designation for tests employed as referred herein.                      **Activity in wells a serial dilution assay. Higher well number indicates     higher activity. The serial dilutions are two-fold.                      

                                      TABLE II                                    __________________________________________________________________________    Biological Activities (Intermediates)                                                                             In Vivo Activity (Guinea Pig)                                                 % Inhibition                                               Cl  C-Late                                                                            Shunt Inhi-                                                                              Intraperitoneal                                                                        Intravenous                                       026*                                                                              035*                                                                              bition 036*                                                                              Time (min.)                                                                            Time (min.)                      Compound         Wells                                                                             Wells                                                                             Wells Cap 50*                                                                            30 60 120                                                                              2  30 120                        __________________________________________________________________________    8,8'-[5-(4-Nitro-2-sulfobenzamido)-                                           1,3-phenylenedicarbonyl]di-1,3,6-                                                              +4  +2  +1    201  -40                                                                              -55                                                                              -74                                                                              -91                                                                              -59                                                                              -51                        naphthalenetrisulfonic acid hepta-                                            sodium salt                                                                   8,8'-[5-(4-Amino-2-sulfobenzamido)-                                           1,3-phenylenedicarbonyl]di-1,3,6-                                                              +6  +3  +2    142  -45                                                                              -61                                                                              -73                                                                              -98                                                                              -79                                                                              -45                        naphthalenetrisulfonic acid hepta-                                            sodium salt                                                                   __________________________________________________________________________     *Code designation for tests employed as referred herein.                      **Activity in wells a serial dilution assay. Higher well number indicates     higher activity. The serial dilutions are two-fold.                      

EXAMPLE 18,8'-[5-(4-Nitro-2-sulfobenzamido)-1,3-phenylenedicarbonyl]di-1,3,6-naphthalenetrisulfonicacid heptasodium salt

A mixture of 10.0 g of 5-nitroisophthalic acid, 50 ml of thionylchloride and 0.2 ml of dimethylformamide is refluxed with stirring for 21/2 hours. The solution is allowed to stand 48 hours at room temperaturethen is evaporated to an oil in vacuo. The evaporation step is repeatedseveral times with cyclohexane and then toluene. Finally hexane is addedand partial evaporation produces crystals. The mixture is cooled, thenfiltered. The crystals are washed with cold hexane to give5-nitroisophthaloyl chloride.

To a solution of 25.5 g of 8-amino-1,3,6-naphthalenetrisulfonic acid,trisodium salt in 100 ml of water and 60 ml of N sodium hydroxide atroom temperature is added 8.13 g of 5-nitroisophthaloyl chloride withabout 25 ml of ether. The mixture is shaken briefly and a second 60 mlportion of N sodium hydroxide is added. The mixture is shaken for 5minutes and a third 60 ml portion of N sodium hydroxide is added. Themixture is shaken for 15 minutes and a 1.0 g portion of the acidchloride is added with a few ml of ether, shaking is resumed for anadditional 45 minutes then the mixture is acidified with 5 ml ofconcentrated hydrochloric acid and extracted with four 150 ml portionsof ether. The aqueous solution is neutralized and is concentrated toabout 50 ml in vacuo at 55° C. The remaining liquid is allowed to standat room temperature for 48 hours and forms a solid which is diluted with125 ml of 80% ethyl alcohol and triturated. The material is filtered andwashed with 80% ethyl alcohol, absolute ethanol and ether, then dried at120° C. for a few hours. The product is then dissolved in 60 ml ofwater, heated on the steam bath and diluted with 300 ml of absoluteethanol. The material is filtered and washed and the final product isthen dried at 120° C. overnight to give8,8'-[(5-nitro-1,3-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonicacid, hexasodium salt.

A mixture of 23.0 g of the preceding product, 150 ml of water and 2.3 gof 10% palladium catalyst on carbon is hydrogenated at room temperaturefor 5 hours at an average pressure of 43 lbs., then is filtered throughdiatomaceous earth and washed with water. The filtrate is thenconcentrated to a small volume in vacuo, absolute ethanol is added andthe resulting oil is triturated until a solid is formed. This materialis filtered and washed with absolute ethanol followed by ether. Theproduct is then oven dried at 120° C. to give8,8'-[(5-amino-m-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonicacid, hexasodium salt.

An 8.65 g portion of the product above, 1.63 g of sodium acetatetrihydrate and 2.2 g of 4-nitro-2-sulfobenzoic acid anhydride in 25 mlof water is stirred for 15 minutes at 0°-5° C. The solution is filtered,the filtrate is acidified with one ml of concentrated hydrochloric acid,warmed on a steam bath and diluted with 120 ml of ethanol. The mixtureis cooled, filtered and the product is washed with 80% aqueous ethanol,ethanol and ether, then is dried by conventional means to give 9.8 g ofthe product of the example as a pale yellow powder.

EXAMPLE 28,8'-]5-(4-Amino-2-sulfobenzamido)-1,3-phenylenedicarbonyl]di-1,3,6-naphthalenetrisulfonicacid heptasodium salt

A mixture of 8.38 g of the product of Example 1, 75 ml of water and 0.5g of 10% palladium on carbon catalyst is hydrogenated at roomtemperature for one hour in a Parr shaker. The resulting mixture isfiltered through diatomacous earth. The filtrate is concentrated to20-25 ml, warmed and diluted with 200 ml of ethanol. The mixture iscooled and the granular precipitate is collected, washed with ethanoland ether then is dried to give 7.8 g of the product of the example as atan powder.

EXAMPLE 38,8',8",8'"Ureylenebis[(2-sulfo-4,1-phenylene)carbonylimino-s-phenenylbis(carbonylimino)]tetra-1,3,6-naphthalenetrisulfonicacid tetradecyl sodium salt

A 5.1 g portion of the product of Example 2 in 25 ml of water plus 850mg of sodium carbonate is phosgenated until acidic. An additional 500 mgof sodium carbonate is added plus 5 ml of water, then phosgene isbubbled in, keeping the solution weakly basic. The solution is warmedand diluted with 100 ml of ethanol to give a gum which solidifies oncooling. The mixture is filtered and precipitate is washed with 77%aqueous ethanol, ethanol and ether to give a tan-yellow powder. Theproduct is dissolved in 30 ml of water and diluted with 60 ml ofethanol. The resulting oil is collected by filtering throughdiatomaceous earth then is dissolved on the filter with 30 ml of water.The resulting aqueous solution is again diluted with 60 ml of ethanoland is triturated with ethanol until a solid is formed. The solid iscollected and dried by conventional means to give 2.2 g of the productof the example as a tan powder.

EXAMPLE 4

    ______________________________________                                        Preparation of Compressed Tablet                                                      Ingredient      mg/Tablet                                             ______________________________________                                        Active Compound         0.5-500                                               Dibasic Calcium Phosphate N.F.                                                                        qs                                                    Starch USP              40                                                    Modified Starch         10                                                    Magnesium Stearate USP  1-5                                                   ______________________________________                                    

EXAMPLE 5

    ______________________________________                                        Preparation of Compressed Tablet - Sustained Action                           Ingredient              mg/Tablet                                             ______________________________________                                        Active Compound         0.5-500 (as acid                                      as Aluminum Lake*, Micronized                                                                         equivalent)                                           Dibasic CaLcium Phosphate N.F.                                                                        qs                                                    Alginic Acid            20                                                    Starch USP              35                                                    Magnesium Stearate USP  1-10                                                  ______________________________________                                         *Complement inhibitor plus aluminum sulfate yeilds aluminum complement        inhibitor. Complement inhibitor content in aluminum lake ranges from          5-30%.                                                                   

EXAMPLE 6

    ______________________________________                                        Preparation of Hard Shell Capsule                                                    Ingredient     mg/Capsule                                              ______________________________________                                        Active Compound        0.5-500                                                Lactose, Spray Dried  qs                                                      Magnesium Stearate     1-10                                                   ______________________________________                                    

EXAMPLE 7

    ______________________________________                                        Preparation of Oral Liquid (Syrup)                                                   Ingredient     % W/V                                                   ______________________________________                                        Active Compound       0.05-5                                                  Liquid Sugar          75.0                                                    Methyl Paraben USP    0.18                                                    Propyl Paraben USP    0.02                                                    Flavoring Agent       qs                                                      Purified Water qs ad  100.0                                                   ______________________________________                                    

EXAMPLE 8

    ______________________________________                                        Preparation of Oral Liquid (Elixir)                                                  Ingredient     % W/V                                                   ______________________________________                                        Active Compound       0.05-5                                                  Alcohol USP           12.5                                                    Glycerin USP          45.0                                                    Syrup USP             20.0                                                    Flavoring Agent       qs                                                      Purified Water qs ad  100.0                                                   ______________________________________                                    

EXAMPLE 9

    ______________________________________                                        Preparation of Oral Suspension (Syrup)                                        Ingredient          % W/V                                                     ______________________________________                                        Active compound     0.05-5                                                    as Aluminum Lake, Micronized                                                                      (acid equivalent)                                         Polysorbate 80 USP  0.1                                                       Magnesium Aluminum Silicate,                                                  Colloidal           0.3                                                       Flavoring Agent     qs                                                        Methyl Paraben USP  0.18                                                      Propyl Paraben USP  0.02                                                      Liquid Sugar        75.0                                                      Purified Water qs ad                                                                              100.0                                                     ______________________________________                                    

EXAMPLE 10

    ______________________________________                                        Preparation of Injectable Solution                                            Ingredient           % W/V                                                    ______________________________________                                        Active Compound      0.05-5                                                   Benzyl Alcohol N.F.  0.9                                                      Water for Injection  100.0                                                    ______________________________________                                    

EXAMPLE 11

    ______________________________________                                        Preparation of Injectable Oil                                                 Ingredient           % W/V                                                    ______________________________________                                        Active Compound      0.05-5                                                   Benzyl Alcohol       1.5                                                      Sesame Oil qs ad     100.0                                                    ______________________________________                                    

EXAMPLE 12

    ______________________________________                                        Preparation of Intra-Articular Product                                        Ingredient           Amount                                                   ______________________________________                                        Active Compound      2-20 mg                                                  NaCl (physiological saline)                                                                        0.9%                                                     Benzyl Alcohol       0.9%                                                     Sodium Carboxymethylcellulose                                                                      1-5%                                                     pH adjusted to 5.0-7.5                                                        Water for Injection qs ad                                                                          100%                                                     ______________________________________                                    

EXAMPLE 13

    ______________________________________                                        Preparation of Injectable Depo Suspension                                     Ingredient          % W/V                                                     ______________________________________                                        Active Compound     0.05-5                                                                        (acid equivalent)                                         Polysorbate 80 USP  0.2                                                       Polyethylene Glycol 4000 USP                                                                      3.0                                                       Sodium Chloride USP 0.8                                                       Benzyl Alcohol N.F. 0.9                                                       HCl to pH 6-8       qs                                                        Water for Injection qs ad                                                                         100.0                                                     ______________________________________                                    

I claim:
 1. A compound of the formula: ##STR4## wherein A is apharmaceutically acceptable salt cation.
 2. The compound according toclaim 1,8,8',8",8'"-ureylenebis[(2-sulfo-4,1-phenylene)carbonylimino-s-phenenyl-bis(carbonylimino)]-tetra-1,3,6-naphthalenetrisulfonicacid tetradecyl sodium salt.